The cause of both battles was the contest for control of the nearby fort of Bellinzona, which at the time happened to be at the point of overlap of the spheres of influence of the Old Swiss Confederacy and the Duchy of Milan. Control of Bellinzona was the strategic key to controlling the Gotthard Pass and the valleys of Ticino and Misox. Uri had won Bellinzona in 1419, but lost it again as a result of the battle of Arbedo of 1422. Uri launched a renewed campaign to regain the valleys in the southern Alps in 1439, and in 1441 forced Milan to yield the Leventina (which had already come under Swiss control in 1430) The unstable situation in the Duchy of Milan with the death of Filippo Maria Visconti in 1447 and the formation of the short-lived Golden Ambrosian Republic encouraged Uri to push forward as far as Bellinzona once again.

Milan charged Condottiere Giovanni della Noce with leading the campaign against the Swiss and re-establish Milanese control over the . Della Noce defeated the force of Uri near Castione, in a battle which lasted for most of the day. The village was burned down, and Uri was forced to retreat to the Misox. Milan secured control over Bellinzona and the Riviera.

A formal peace treaty was enacted in 1450, and in 1466, Milan agreed to grant the Leventina to Uri permanently. The defeat at Castione halted Swiss expansion south of the Alps for several decades, until the Confederate campaign of 1478, and the Swiss victory in the Battle of Giornico in 1487.

In Swiss historiography, the account of the battle of Castione was corrupted, because historian (1840–1914) confused it with the battle of Castiglione Olona (1450), which led to the dissolution of the Ambrosian Republic. Proper identification of the battle was left to historians of the 20th century (Chiesi 1979).